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Insights on the Role of Stem Cells in Tendon Tissue Engineering: From Basic Science to Translational Medicine

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 15 June 2024 | Viewed by 3242

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Special Issue Editors

Dr. Maria Camilla Ciardulli

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Guest Editor

Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi, Italy
Interests: human bone marrow mesenchymal stem cells; human Wharton’s Jelly mesenchymal stem cells; tendon stem/progenitor cells; 3D bioengineered scaffolds; tendon regeneration; in vitro models; immunomodulation, tissue engineering; regenerative medicine; drug delivery; bioreactor systems

Prof. Dr. Nicola Maffulli

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Guest Editor

Laboratory of Translational Medicine, Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi, Italy
Interests: sports trauma injury, joint replacement, hand & rheumatoid surgery, & adult & paediatric orthopaedics; surgical techniques in the field of knee, foot and ankle, and sports surgery; soft tissues problems
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Special Issue Information

Dear Colleagues,

Tendon injuries remain difficult to manage due to their poor healing ability, ascribable to a low cellularity and hypo-vascularity, leading to scar tissue formation, instead of organized extracellular matrix, thus affecting tendon biomechanical functionality. The currently applied treatments, including exercise, drug delivery, and surgical procedures, are not sufficient for a complete regeneration, which implies the development of promising strategies with the aim to deal with this pathology. To this end, cell-based therapy and tissue engineering represent challenging approaches for the regeneration of damaged tendon tissues with the aim to stimulate self-regeneration or to produce functional implantable tissue replacements. In particular, tissue engineering belongs to a multidisciplinary field that involves the use of a combination of key factors, such as cells, scaffolds, and biochemical and mechanical inputs i) to realize in vitro models and ii) to produce functional tissue-like constructs able to support damaged tissue, inducing its functional recovery. The combinatory effect of two or more factors seems to play a key role in boosting the tendon differentiation of stem cells.

This Special Issue will cover a selection of papers related to the use of stem cells in the development of in vitro 3D bioengineered complex models to understand the specific behavior of tendon healing and regeneration, as well as their translational potential in in vivo models.

Dr. Maria Camilla Ciardulli
Prof. Dr. Nicola Maffulli
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

stem cells
tenogenic differentiation
3D in vitro tendon models
immunomodulation
biomimetic scaffolds
in vivo tendon models
dynamic cultures

Published Papers (4 papers)

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Research

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19 pages, 8830 KiB

Open AccessArticle

Assessing Bioprinted Functionalized Grafts for Biological Tendon Augmentation In Vitro

by Cristina Del Amo, Miguel Perez-Garrastachu, Ines Jauregui, Xabier Llama-Pino and Isabel Andia

Int. J. Mol. Sci. 2024, 25(9), 4752; https://doi.org/10.3390/ijms25094752 - 26 Apr 2024

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Abstract

Tendinopathy, characterized by inflammatory and degenerative changes, presents challenges in sports and medicine. In addressing the limitations of conservative management, this study focuses on developing tendon grafts using extrusion bioprinting with platelet-rich plasma (PRP)-infused hydrogels loaded with tendon cells. The objective is to understand paracrine interactions initiated by bioprinted tendon grafts in either inflamed or non-inflamed host tissues. PRP was utilized to functionalize methacrylate gelatin (GelMA), incorporating tendon cells for graft bioprinting. Bioinformatic analyses of overexpressed proteins, predictive of functional enrichment, revealed insights into PRP graft behavior in both non-inflamed and inflamed environments. PRP grafts activated inflammatory pathways, including Interleukin 17 (IL-17), neuroinflammation, Interleukin 33 (IL-33), and chemokine signaling. Interleukin 1 beta (IL-1b) in the graft environment triggered p38 mitogen-activated protein kinase (MAPK) signaling, nuclear factor kappa light chain enhancer of activated B cells (NF-kB) canonical pathway, and Vascular Endothelial Growth Factor (VEGF) signaling. Biological enrichment attributed to PRP grafts included cell chemotaxis, collagen turnover, cell migration, and angiogenesis. Acellular PRP grafts differed from nude grafts in promoting vessel length, vessel area, and junction density. Angiogenesis in cellular grafts was enhanced with newly synthesized Interleukin 8 (IL-8) in cooperation with IL-1b. In conclusion, paracrine signaling from PRP grafts, mediated by chemokine activities, influences cell migration, inflammation, and angiogenic status in host tissues. Under inflammatory conditions, newly synthesized IL-8 regulates vascularization in collaboration with PRP. Full article

(This article belongs to the Special Issue Insights on the Role of Stem Cells in Tendon Tissue Engineering: From Basic Science to Translational Medicine)

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19 pages, 9352 KiB

Open AccessArticle

ZIM1 Combined with Hydrogel Inhibits Senescence of Primary PαS Cells during In Vitro Expansion

by Yueming Tian, Menglong Hu, Xuenan Liu, Xu Wang, Dazhuang Lu, Zheng Li, Yunsong Liu, Ping Zhang and Yongsheng Zhou

Int. J. Mol. Sci. 2023, 24(11), 9766; https://doi.org/10.3390/ijms24119766 - 05 Jun 2023

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Abstract

Bone marrow stem cells (BMSCs) are a promising source of seed cells in bone tissue engineering, which needs a great quantity of cells. Cell senescence occurs as they are passaged, which could affect the therapeutic effects of cells. Therefore, this study aims to explore the transcriptomic differences among the uncultured and passaged cells, finding a practical target gene for anti-aging. We sorted PαS (PDGFR-α⁺SCA-1⁺CD45^-TER119^-) cells as BMSCs by flow cytometry analysis. The changes in cellular senescence phenotype (Counting Kit-8 (CCK-8) assay, reactive oxygen species (ROS) test, senescence-associated β-galactosidase (SA-β-Gal) activity staining, expression of aging-related genes, telomere-related changes and in vivo differentiation potential) and associated transcriptional alterations during three important cell culture processes (in vivo, first adherence in vitro, first passage, and serial passage in vitro) were studied. Overexpression plasmids of potential target genes were made and examed. Gelatin methacryloyl (GelMA) was applied to explore the anti-aging effects combined with the target gene. Aging-related genes and ROS levels increased, telomerase activity and average telomere length decreased, and SA-β-Gal activities increased as cells were passaged. RNA-seq offered that imprinted zinc-finger gene 1 (Zim1) played a critical role in anti-aging during cell culture. Further, Zim1 combined with GelMA reduced the expression of P16/P53 and ROS levels with doubled telomerase activities. Few SA-β-Gal positive cells were found in the above state. These effects are achieved at least by the activation of Wnt/β-catenin signaling through the regulation of Wnt2. The combined application of Zim1 and hydrogel could inhibit the senescence of BMSCs during in vitro expansion, which may benefit clinical application. Full article

(This article belongs to the Special Issue Insights on the Role of Stem Cells in Tendon Tissue Engineering: From Basic Science to Translational Medicine)

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Review

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22 pages, 950 KiB

Open AccessReview

Recent Advances in the Use of Stem Cells in Tissue Engineering and Adjunct Therapies for Tendon Reconstruction and Future Perspectives

by Paweł Dec, Małgorzata Żyłka, Piotr Burszewski, Andrzej Modrzejewski and Andrzej Pawlik

Int. J. Mol. Sci. 2024, 25(8), 4498; https://doi.org/10.3390/ijms25084498 - 19 Apr 2024

Viewed by 275

Abstract

Due to their function, tendons are exposed to acute injuries. This type of damage to the musculoskeletal system represents a challenge for clinicians when natural regeneration and treatment methods do not produce the expected results. Currently, treatment is long and associated with long-term complications. In this review, we discuss the use of stem cells in the treatment of tendons, including how to induce appropriate cell differentiation based on gene therapy, growth factors, tissue engineering, proteins involved in regenerative process, drugs and three-dimensional (3D) structures. A multidirectional approach as well as the incorporation of novel components of the therapy will improve the techniques used and benefit patients with tendon injuries in the future. Full article

(This article belongs to the Special Issue Insights on the Role of Stem Cells in Tendon Tissue Engineering: From Basic Science to Translational Medicine)

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16 pages, 782 KiB

Open AccessReview

Cell-Based Therapies for Rotator Cuff Injuries: An Updated Review of the Literature

by Nicholas Hooper, Anuj Marathe, Nitin B. Jain and Prathap Jayaram

Int. J. Mol. Sci. 2024, 25(6), 3139; https://doi.org/10.3390/ijms25063139 - 08 Mar 2024

Viewed by 827

Abstract

This review focuses on non-surgical treatment options for rotator cuff injuries and highlights the potential of mesenchymal stem cells (MSCs) as a potential regenerative approach. MSCs, sourced from various tissues like bone marrow and adipose tissue, exhibit promising mechanisms in vitro, influencing tendon-related gene expression and microenvironment modulation. Animal studies support this, showcasing MSCs’ ability to reduce inflammation, improve tissue remodeling, and enhance repaired tendon strength. Human trials, while varied and limited, suggest that MSCs might lower retear rates and enhance post-repair outcomes, but randomized controlled trials yield mixed results, emphasizing the necessity for standardized investigations. Ultimately, while cell-based therapies demonstrate an excellent safety profile, more rigorous clinical trials are necessary to determine their efficacy in improving patient outcomes and achieving lasting structural changes in rotator cuff injuries. Full article

(This article belongs to the Special Issue Insights on the Role of Stem Cells in Tendon Tissue Engineering: From Basic Science to Translational Medicine)

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